Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collagen stimulates the activation of phosphatidylinositol (PI)-specific phospholipase C (EC 3.1.4.10) in human platelets, as manifested by the disappearance of PI, the transient formation of diacylglycerol (DG), and release of myoinositol. Platelets exposed to collagen also form lysophosphatidylinositol (LPI). Maximum formation of DG occurs within 60 s of the addition of collagen and is in proportion to the concentration of collagen provided, up to 100 micrograms/2 x 10(9) platelets/ml. Hydrolysis of PI, formation of DG, and release of arachidonic acid are all inhibited approximately 68% by aspirin or indomethacin, both of which inhibit platelet cyclooxygenase. This inhibition is reversed by the product of cyclooxygenase activity, 15-hydroxy - 9 alpha,11 alpha - peroxidoprosta - 5,13 - dienoic acid (PGH2), or by the PGH2 analogue and agonist, U-46619. The counteracting effects of either PGH2 or the PGH2 analogue can be blocked, in turn, by a PGH2 antagonist, U-51605. Neither PGH2 nor its stable analogue is, by itself, an efficient stimulus for PI breakdown to DG and LPI in platelets. However, in conjunction with collagen, these agents synergistically promote the net breakdown of PI and the release of arachidonic acid in aspirin-treated platelets. Our findings thereby imply that PGH2 has an important role in regulating both the release of its precursor, arachidonic acid, and the metabolism of PI induced by collagen. Dibutyryl cyclic AMP or prostaglandin D2 (PGD2), a prostaglandin that elevates concentrations of cAMP in platelets by stimulating adenylate cyclase, inhibits the hydrolysis of PI induced by collagen by 70%. The activation of PI metabolism by collagen appears to be inhibited by cAMP independently of any effects of this inhibitor on the formation of PGH2.
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PMID:Synergistic activation by collagen and 15-hydroxy-9 alpha,11 alpha-peroxidoprosta-5,13-dienoic acid (PGH2) of phosphatidylinositol metabolism and arachidonic acid release in human platelets. 681 11

A fibrogenic factor which stimulates collagen production without cell proliferation of rat skin fibroblast cultures was isolated from CCl4-damaged rat liver. (1) The factor was isolated from saline extracts of CCl4-induced fibrotic rat liver and fractionated by Sephadex G-50S gel filtration and DEAE-cellulose chromatography. The original extract produced a 6-fold increase in collagen synthesis and the active factor eluted from gel filtration columns in a region corresponding to 5000 daltons. (2) The active factor was destroyed by heat (57 degrees C, 30 min), phospholipase C digestion, but was insensitive to proteolytic enzymes or phospholipase A. Chemical analysis of the partially purified factor revealed relatively high quantities of phosphorus (3%) and low quantities of protein (13.3%), neutral sugar (1.9%) and uronic acid (4.9%). The possibility of this component being a complex phospholipid containing polypeptide is suggested. (3) Fibrogenic properties of the isolated factor was enhanced by apparent oxidation in air, to a more active, yet insoluble complex. Attempts to solubilize the oxidized product completely destroyed its biological activity.
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PMID:Isolation and characterization of a fibrogenic factor from CCl(4)-damaged rat liver. 711 58

Thermally modified human C-reactive protein (H-CRP) and IgG (AHGG) each activate isolated human platelets to reactions of aggregation and secretion. As these molecules exhibit many functional similarities, we questioned whether they might also share a receptor on the platelet membrane. Neither plasmin nor phospholipase C altered the platelet response to H-CRP or AHGG, although these reagents enhanced the platelet expression to acid soluble collagen (ASC). Conversely, chymotrypsin treatment of platelets resulted in an elevated response to each H-CRP and AHGG, but not to ASC. These data suggest that the H-CRP and AHGG platelet receptors share characteristics which contrast with those of the receptor for collagen. However, monomeric IgG, which can bind with the platelet and inhibit the response to AHGG, exerted no effect on the platelet response to H-CRP. Further, a functional receptor for thermally modified human or rabbit CRP was detected on rabbit platelets in the absence of a demonstrable Fc receptor for aggregated IgG. These data indicate that the platelet receptors for the modified forms of CRP and IgG are distinct.
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PMID:Comparison of the enzymatic sensitivities of the platelet receptor for human C-reactive protein and its functional relationship to the platelet IgG Fc receptor. 717 7

Serine esterase inhibitors (phenylmethanesulfonyl fluoride, 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) fluoride, 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, or p-nitrophenyl anthranilate) blocked the production of malonyldialdehyde by platelets induced with a variety of stimuli (including thrombin, trypsin, collagen, and A23187). These inhibitors did not block malonyldialdehyde production by platelets from exogenous arachidonic acid. Those inhibitors studied in greater detail (phenylmethanesulfonyl fluoride and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate) were shown to inhibit the release of [1-14C]arachidonic acid from phosphatidylinositol and phosphatidylcholine in intact platelets but not the conversion of arachidonic acid to thromboxanes, prostaglandins, or hydroxyfatty acids. These inhibitors also blocked the stimulus-induced production of [32P]phosphatidic acid in intact platelets. Both arachidonic acid release from phosphatidylinositol and phosphatidic acid production have been reported to depend on the production of diglyceride by the action on the phosphatidylinositol-specific phospholipase C.f a phosphatidylinositol-specific phospholipase C. That enzyme in the soluble fraction from disrupted platelets was inhibited at concentrations of serine esterase inhibitors which block arachidonic acid release in intact platelets. These results indicate that serine esterase inhibitors block the stimulus-induced mobilization of arachidonic acid in platelets at least in part by their action o
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PMID:Serine esterase inhibitors block stimulus-induced mobilization of arachidonic acid and phosphatidylinositide-specific phospholipase C activity in platelets. 739 Oct 2

Endogenous phospholipid metabolism in stimulated human platelets was studied by phosphorus assay of major and minor components following separation by two-dimensional thin-layer chromatography. This procedure obviated the use of radioactive labels. Extensive changes were found in quantities of phosphatidylinositol (PI) and phosphatidic acid (PA) as a consequence of thrombin or collagen stimulation. Thrombin addition was followed by rapid alterations in the amount of endogenous PI and PA. The decrease in PI was not precisely reciprocated by an increase in PA when thrombin was the stimulus. This apparent discrepancy could be explained by removal of a transient intermediate in PI metabolism, such as diglyceride, formed by PI-specific phospholipase C (Rittenhouse-Simmons, S., J. Clin. Invest.63: 580-587, 1979). Diglyceride would be unavailable for PA formation by diglyceride kinase, if hydrolyzed by diglyceride lipase (Bell, R. L., D. A. Kennerly, N. Stanford, and P. W. Majerus. Proc. Natl. Acad. Sci. U. S. A.76: 3238-3241, 1979) to yield arachidonate for prostaglandin endoperoxide formation. Thrombin-treated platelets also accumulated lysophospho-glycerides. Specifically, lysophosphatidyl ethanolamines accumulated within 15s following thrombin addition. Fatty acid and aldehyde analysis indicated phospholipase A(2) activity, with an apparent preference for diacyl ethanolamine phosphoglycerides. In the case of collagen, these changes occurred concomitantly with aggregation and consumption of oxygen for prostaglandin endoperoxide formation.THESE STUDIES OF ENDOGENOUS PHOSPHOLIPID METABOLISM PROVIDE INFORMATION SUPPORTING THE EXISTENCE OF TWO PREVIOUSLY POSTULATED PATHWAYS FOR LIBERATION OF ARACHIDONIC ACID FROM PLATELET PHOSPHOLIPIDS: (a) the combined action of PI-specific phospholipase C plus diglyceride lipase yielding arachidonate derived from PI; and (b) a phospholipase A(2) acting primarily on diacyl ethanolamine phosphoglyceride.
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PMID:Phospholipid metabolism in stimulated human platelets. Changes in phosphatidylinositol, phosphatidic acid, and lysophospholipids. 740 Mar 15

Activation of human platelets by cross-linking of the platelet low-affinity IgG receptor, the Fc gamma receptor IIA (Fc gamma-RIIA), or by collagen is associated with rapid phosphorylation on tyrosine of the non-receptor tyrosine kinase syk. Phosphorylation is still observed, albeit sometimes reduced, in the presence of a combination of a protein kinase C inhibitor, Ro 31-8220, and the intracellular calcium chelator, BAPTA-AM, demonstrating independence from phosphoinositide-specific phospholipase C (PLC) activity. In contrast, the combination of Ro 31-8220 and BAPTA-AM completely inhibits phosphorylation of syk in thrombin-stimulated platelets. Phosphorylation of syk increases its autophosphorylation activity measured in a kinase assay performed on syk immunoprecipitates. Fc gamma-RIIA also undergoes phosphorylation in syk immunoprecipitates from platelets activated by cross-linking of Fc gamma-RIIA but not by collagen, suggesting that it associates with the kinase. Consistent with this, tyrosine-phosphorylated Fc gamma-RIIA is precipitated by a glutathione S-transferase (GST) fusion protein containing the tandem src homology (SH2) domains of syk from Fc gamma-RIIA- but not collagen-activated cells. Two uncharacterized tyrosine-phosphorylated proteins of 40 and 65 kDa are uniquely precipitated by a GST fusion protein containing the tandem syk-SH2 domains in collagen-stimulated platelets. A peptide based on the antigen recognition activation motif (ARAM) of Fc gamma-RIIA, and phosphorylated on the two tyrosine residues found within this region, selectively binds syk from lysates of resting platelets; this interaction is not seen with a non-phosphorylated peptide. Kinase assays on Fc gamma-RIIA immunoprecipitates reveal the constitutive association of an unidentified kinase activity in resting cells which phosphorylates a 67 kDa protein. Syk is not detected in Fc gamma-RIIA immunoprecipitates from resting cells but associates with the receptor following activation and, together with Fc gamma-RIIA, is phosphorylated in the kinase assay in vitro. These results demonstrate that syk is activated by Fc gamma-RIIA cross-linking and collagen, independent of PLC, suggesting that it may have an important role in the early events associated with platelet activation. The association of syk with Fc gamma-RIIA appears to be mediated through the tandem SH2 domains in syk and the ARAM motif of Fc gamma-RIIA. A similar interaction may underlie the response to collagen, suggesting that its signalling receptor contains an ARAM motif.
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PMID:Syk interacts with tyrosine-phosphorylated proteins in human platelets activated by collagen and cross-linking of the Fc gamma-IIA receptor. 748 83

Platelet glycoprotein (GP) VI is a so-far uncharacterized 62-kDa membrane protein, whose deficiency results in selective impairment in collagen-induced platelet aggregation. Our group previously reported a human polyclonal antibody (anti-p62 IgG) that induces activation of normal, but not of GPVI-deficient, platelets in an Fc-independent manner. The F(ab')2 fragments of this antibody (F(ab')2-anti-p62) stimulated tyrosine phosphorylation of numerous proteins, which was not prevented even in the presence of cAMP-increasing agents such as prostacyclin. Pretreatment of platelets with the protein-tyrosine kinase (PTK) inhibitor tyrphostin A47 completely abolished F(ab')2-anti-p62-induced platelet aggregation in parallel with dose-dependent inhibition of protein-tyrosine phosphorylation, indicating an essential requirement of PTK activity for generating GPVI-mediated signaling. We found that two cytosolic PTKs, c-Src and Syk, became rapidly activated in response to F(ab')2-anti-p62 in a way insensitive to elevation of cAMP. In contrast, in the presence of prostacyclin, F(ab')2-anti-p62 did not stimulate tyrosine phosphorylation of the focal adhesion kinase. cAMP-insensitive activation of c-Src and Syk was also observed in collagen but not thrombin-stimulated platelets. Moreover, either F(ab')2-anti-p62 or collagen stimulated cAMP-insensitive tyrosine phosphorylation of phospholipase C-gamma 2. These results indicate that the receptor-mediated activation of several PTKs in platelets is regulated through a cAMP-sensitive or -insensitive mechanism depending on the nature of each stimulus, and also suggest that GPVI engagement is coupled to cAMP-insensitive activation of c-Src and Syk accompanied by tyrosine phosphorylation of numerous substrates including phospholipase C-gamma 2 in a manner similar to collagen stimulation.
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PMID:Cyclic AMP-insensitive activation of c-Src and Syk protein-tyrosine kinases through platelet membrane glycoprotein VI. 749 87

The iodoplatinate (IP) reaction, a selective method for visualization of phospholipids, was applied to the predentine and dentine of rat incisors and compared with malachite green aldehyde (MG) fixation/staining. Spot tests indicated (1) that IP specifically stains phospholipids, but not amino acids, displaying as do phospholipids, quaternary ammonium groups; and (2) phosphatidylserine and sphingomyelin were also stained by MGA. Although this reagent is known to interact with phosphorus, phosphoproteins remained unstained. In the rat incisor, an IP-positive network including granules and thin filaments was seen in predentine in the inter-collagen spaces, in many cases closely associated with collagen fibres and their periodic striations. In dentine, positively stained needle-like structures were located along individual collagen fibres, or at the surface of groups of collagen fibres. This staining pattern was unchanged on sections of material pretreated with acetone, whereas the staining was abolished or markedly reduced when the samples were treated either with chloroform/methanol or phospholipase C prior to the IP reaction. Pretreatment of the samples with hyaluronidase promoted subsequent diffusion of the staining. A very similar staining pattern was observed with MGA, in accordance with earlier reports. The present findings validate the histochemical results reported previously on the distribution and potential role(s) of phospholipids in dentine biomineralization.
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PMID:Iodoplatinate visualization of phospholipids in rat incisor predentine and dentine, compared with malachite green aldehyde. 751 28

Collagen is an important primary stimulus of platelets during the process of hemostasis. As with many other platelet stimuli, collagen signal transduction involves the hydrolysis of inositol phospholipids; however, the mechanisms which underlies this event is not well understood. Neither the collagen receptor nor the isoform of phospholipase C that is activated have been identified. We report that collagen-activation of platelets induces tyrosine phosphorylation of phospholipase C-gamma 2 but not phospholipase C-gamma 1. We also show that the platelet low affinity Fc receptor (Fc gamma RII), which mediates activation of platelets by immune complexes, and wheat germ agglutinin, which binds non-specifically to glycoprotein, stimulate phospholipase C-gamma 2 tyrosine phosphorylation. In contrast, we could not detect phospholipase C-gamma 2 tyrosine phosphorylation in platelets stimulated by either thrombin or a stable thromboxane A2 analogue, U46619.
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PMID:Collagen stimulates tyrosine phosphorylation of phospholipase C-gamma 2 but not phospholipase C-gamma 1 in human platelets. 752 95

Forty strains of methicillin-resistant Staphylococcus aureus (MRSA) were divided on the basis of their epidemiologic behavior into two subgroups, sporadic MRSA (SMRSA) and epidemic MRSA (EMRSA) strains. The strains were examined for binding of 125I-labelled fibronectin, vitronectin, collagen, Fc fragments of immunoglobulin G, and fibrinogen. A significant difference between EMRSA and SMRSA strains was found for binding of 125I-labelled fibrinogen and for Fc fragments of immunoglobulin G, (P < 0.05). No significant difference in the binding of 125I-labelled fibronectin and collagen was found between EMRSA and SMRSA strains. The binding of 125I-labelled vitronectin to MRSA strains was found to be aspecific. Capsular serotypes of the strains were determined with monoclonal antibodies against capsular types 5 and 8. Strains could be divided into the following four groups: types 5, 8, and 5/8 and nontypeable. More nontypeable strains were found in the EMRSA group (66.6%). Significantly more EMRSA strains (79%) than SMRSA strains (44%) produced alpha-toxin (P < 0.025). Logistic regression analysis using a combination of the parameters 125I-labelled immunoglobulin G binding, capsular type, and alpha-toxin production predicted the epidemic character with a sensitivity of 83% and a specificity of 75%.
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PMID:Phenotypic characterization of epidemic versus sporadic strains of methicillin-resistant Staphylococcus aureus. 754 78


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